This study evaluates an accelerated schedule of theta-burst stimulation using a transcranial magnetic stimulation device for treatment-resistant depression. In a double-blind, randomized, sham-controlled fashion, half the participants will receive accelerated theta-burst stimulation while half will receive sham treatment.

Repetitive transcranial magnetic stimulation (rTMS) is an established therapy for treatment-resistant depression. The approved method for treatment is 10Hz stimulation for 40 min over the left dorsolateral prefrontal cortex (L-DLPFC). This methodology has been effective in real world situations. The limitations of this approach include the duration of the treatment (approximately 40 minutes per treatment session, 5 days per week, for 4-8 weeks). Recently, we have pursued modifying the treatment parameters to reduce treatment times with an accelerated treatment paradigm with great preliminary success. This study aims to further study our accelerated protocol and examine changes in neuroimaging biomarkers.

Dr. Nolan Williams is the Principle Investigator on the grant associated for this study and so is listed as Study Director on the study record.

Inclusion Criteria:

1. Male or Female, between the ages of 22 and 65 at the time of screening.
2. Able to read, understand, and provide written, dated informed consent prior to screening. Proficiency in English sufficient to complete questionnaires / follow instructions during fMRI assessments and aiTBS interventions. Stated willingness to comply with all study procedures, including availability for the duration of the study, and to communicate with study personnel about adverse events and other clinically important information.
3. Currently diagnosed with Major Depressive Disorder (MDD) and meets criteria for a Major Depressive Episode, according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5).
4. Medical records confirming a history of moderate to severe treatment-resistance as defined by a score of 7-14 on the Maudsley Staging Method (MSM3).
5. MADRS score of ≥20 at screening (Visit 1).
6. TMS naive.
7. Access to ongoing psychiatric care before and after completion of the study.
8. Access to clinical rTMS after study completion.
9. Must be on a stable antidepressant therapeutic regimen for 6 weeks prior to study enrollment and agree to continue this regimen throughout the study period.
10. In good general health, as evidenced by medical history.
11. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation.
12. Agreement to adhere to Lifestyle Considerations throughout study duration.

Lifestyle considerations:

1. Abstain from becoming pregnant from the screening visit (Visit 1) until after the final study visit (Visit 9).
2. Continue usual intake patterns of caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) without significant change for the duration of the study.
3. Abstain from alcohol for at least 24 hours before the start of each MRI and TMS session. Participants who use tobacco products will be informed that use will be allowed only in between intervention sessions.

Exclusion Criteria:

1. Pregnancy
2. Primary psychiatric condition other than MDD requiring treatment except stable comorbid anxiety disorder
3. History of or current psychotic disorder or bipolar disorder
4. Severe borderline personality disorder.
5. Diagnosis of Intellectual Disability or Autism Spectrum Disorder
6. Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal
7. Urine screening test positive for illicit substances
8. Active suicidal ideation (defined as an MSSI > 8) or a suicide attempt (as defined by the C-SSRS) within the past one year
9. Any history of ECT (greater than 8 sessions) without meeting responder criteria
10. Recent (within 4 weeks of any clinical effect) or concurrent use of rapid acting antidepressant agent (i.e., ketamine or a course of ECT)
11. History of significant neurologic disease, including dementia, Parkinson's or Huntington's disease, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma
12. Untreated or insufficiently treated endocrine disorder.
13. Contraindication to receiving rTMS (e.g., metal in head, history of seizure, known brain lesion)
14. Contraindication to MRI (ferromagnetic metal in their body)
15. Treatment with another investigational drug or other intervention within the study period
16. Depth-adjusted aiTBS treatment dose > 65% maximum stimulator output (MSO)
17. Unstable symptoms between screening and baseline as defined by a ≥ 30% change in MADRS-S score.
18. Any other condition deemed by the PD to interfere with the study or increase risk to the participant

3 years